Making sense of flavivirus non-strctural protein 1 in innate immune evasion and inducing tissue-specific damage

Flaviviruses include medically important mosquito-borne pathogens, such as Zika virus (ZIKV), Japanese encephalitis virus (JEV), dengue virus (DENV) and West Nile virus (WNV), that cause hundreds of millions of infections each year. Currently, there are no approved effect therapies against mosquito-borne flaviviruses. The flaviviruses encoded nonstructural protein 1 (NS1) is a secreted glycoprotein widely involved in viral replication, immune evasion, and directly causing tissue-specific damage during flaviviruses infection. Upon viral infection of host cell, NS1 can be found in multiple oligomeric forms and include a dimer on the cell surface, and a soluble secreted hexameric lipoparticle. In the recent decade, the detailed crystal structure of several flaviviruses NS1 have been determined and unraveled its broader and deeper functions. Consistent with the potential immune function revealed by its structure, NS1 is involved in the escaping of host signal immune pathway mediated by pattern recognition receptors (PRRs), including RIG-I-like receptors (RLR(S)) and Toll-like receptors (TLRs). Moreover, the flavivirus NS1 is efficiently secreted by infected cells and circulates in the blood of the host to directly induce specific tissues damage. The NS1 of ZIKV, JEV and WNV changes the permeability of brain microvascular endothelial cell to cause endothelial cell dysfunction and promote virus pathogenesis. DENV NS1 can induce systemic tissues damage in humans through multiple strategies. Mutations of several key amino acids in NS1 can reduce the neurovirulence of the flavivirus. In this article, we provide an overview of the latest research on this fascinating protein in these disparate areas.